Submissions for variant NM_182961.4(SYNE1):c.275T>C (p.Ile92Thr) (rs1007703591)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521352	SCV000619400	uncertain significance	not provided	2017-07-31	criteria provided, single submitter	clinical testing	The I92T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I92T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with SYNE1-related disorders (Stenson et al., 2014).
Invitae	RCV001035806	SCV001199143	uncertain significance	Spinocerebellar ataxia, autosomal recessive 8; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2019-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with threonine at codon 92 of the SYNE1 protein (p.Ile92Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SYNE1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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